SUN-065 - Cushing'S Disease from Metastatic Pituitary Neuroendocrine Tumor as A Manifestation of Li Fraumeni Syndrome Due to P53 Mutation: First Case Report

Background: Most pituitary neuroendocrine tumors (PitNETs) are indolent; metastatic PitNET is exceptional (0.1 to 0.2% of PitNETs). Li-Fraumeni syndrome (LFS) is autosomal dominant due to germline TP53 pathogenic variants, classically causing early onset breast cancer, sarcomas, central nervous system (CNS) tumors, leukemia, and adrenocortical carcinoma; rare neuroendocrine tumors (e.g., pancreatic NET) occur. Somatic TP53 variants are enriched in aggressive ACTH secreting PitNETs, supporting a link between impaired TP53 genome surveillance and malignant corticotroph transformation. We report the first metastatic ACTH secreting PitNET in LFS.

Case: A 59 year old woman with LFS (prior squamous and basal cell skin cancers and ductal carcinoma in situ, in remission) was referred in early 2024 with rapid weight gain, worsening hypertension, hypokalemia, and proximal weakness. Biochemical evaluation demonstrated a median urinary free cortisol of ~10x ULN; 1 mg overnight DST unsuppressed (AM cortisol 664 nmol/L); and a markedly elevated baseline ACTH at 99 pmol/L (RR 1.3 to 13), consistent with severe ACTH dependent neoplastic hypercortisolism. Pituitary MRI showed no sellar lesion, but IPSS demonstrated a central ACTH gradient; Gallium-68 PET and whole body CT/MRI showed no ectopic source, supporting pituitary origin. Ketoconazole was titrated while planning transsphenoidal surgery. Despite initial biochemical control, cortisol rose in September; ultrasound for rapidly rising liver enzymes revealed multiple new hypoechoic liver lesions, and repeat sellar MRI showed a new 2 cm infiltrative lesion. Multidisciplinary care included anticoagulation and antibiotics. Transsphenoidal resection was uncomplicated but hypercortisolism persisted. Pathology revealed a ACTH PitNET with high grade features (Ki67 ~60%). Liver biopsy: morphologically similar tumor lacking ACTH and T-PIT, confirming metastatic disease with dedifferentiation. IHC showed nuclear p53 >80% (mutant pattern); MGMT promoter methylation suggested temozolomide sensitivity. Options (IV etomidate, bilateral adrenalectomy, capecitabine plus temozolomide) were offered, but the patient chose medical assistance in dying (MAID) due to suffering.

Conclusion: This is the first reported metastatic ACTH secreting PitNET in Li-Fraumeni syndrome, suggesting germline TP53 mutations may predispose to aggressive corticotroph PitNETs and warrant heightened vigilance.

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